Biology subjects

Gordon, S. M.

Publications and source records attributed to Gordon, S. M..

11 recordsLinked to original sources

bioRxiv2026

Preserved CETP Activity and Early Serum Amyloid A are Associated with Improved Outcomes in Sepsis-Associated ARDS

Background: Sepsis is a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection. It is a leading cause of in-hospital mortality. The multicenter Acute Respiratory Distress Syndrome Network Statins for Acutely Injured Lungs from Sepsis (ARDSNet-SAILS) trial found that rosuvastatin (RS) did not improve clinical outcomes in patients with sepsis-associated ARDS and may increase hepatic and renal dysfunction. We evaluated associations of plasma cholesterol ester transfer protein (CETP) activity and Serum Amyloid A (SAA) levels with survival and clinical outcomes using plasma samples and clinical data from ARDSNet-SAILS trial. Methods: This secondary analysis included clinical data and plasma samples from 471 ARDSNet-SAILS participants, randomized to placebo (PL) or RS. Plasma CETP activities and SAA levels were measured at enrollment (Day 0, n=466) and Days 3 (n=425) and 6 (n=342). Treatment effects were assessed using linear mixed models, and associations with survival and outcomes using Cox, linear, beta-binomial, and zero-inflated negative binomial regression models. Results: CETP activities were significantly higher in the survivors compared to non-survivors on days 0, 3, and 6 of analysis, in both the treatment groups (p<0.01). Higher Day 0 and Day 3 CETP activities in PL patients independently predicted improved survival, with every 3-unit increase in activity associated with 18 to 19% lower mortality risk. In the RS treatment group, higher CETP at Day 0, Day 3, and Day 6 was significantly associated with reduced hazard of mortality (p=0.039, 0.005, and 0.022, and hazard ratios = 0.87, 0.82, and 0.80, respectively, for Days 0, 3, and 6). Higher CETP values on Days 3 and 6 were also significantly negatively associated with APACHE score and positively associated with increased renal dysfunction-free days (p=0.001). Plasma SAA levels decreased significantly over time in both treatment groups (p<0.0001). In the PL group, higher plasma SAA levels were associated with a lower hazard of mortality. Accordingly, survivors had significantly higher plasma SAA levels than non-survivors at Day 0 (p=0.005). Higher SAA levels at Days 0 and 3 were also inversely correlated with APACHE scores, while Day 0 SAA levels were positively associated with overall organ dysfunction-free days (p=0.002). In contrast, in the RS group, higher plasma SAA levels were associated with an increased hazard of mortality, reaching statistical significance at Day 6 (p<0.01). Despite this, higher SAA levels in the RS group were positively associated with renal dysfunction-free days (Day 3, p=0.004; Day 6, p=0.006), hepatic dysfunction-free days (Days 0, 3, and 6; all p[≤]0.001), and overall organ dysfunction-free days (Day 0, p=0.017; Days 3 and 6, both p<0.001). Analysis of SAA levels in FPLC fractions demonstrated higher SAA levels in the HDL fraction among survivors compared with non-survivors in the PL group on Days 0 and 3; however, this difference was not observed in the RS group. Conclusion: Taken together, these findings identify plasma CETP activities and early SAA levels as stable prognostic biomarkers associated with improved survival and reduced disease severity in sepsis. However, while both CETP activity and SAA levels were unaffected by RS treatment, it appeared to modify the association between SAA and mortality.

biochemistry↗

bioRxiv2026

Identification of scavenger receptor BI as a scavenger of free heme that is essential for protection against hemolysis

Severe hemolysis is a life-threatening condition with limited therapeutic options. Although haptoglobin and hemopexin sequester hemoglobin and heme, these protective systems are rapidly saturated during acute hemolysis, leading to the accumulation of cytotoxic free heme. In this study, we identify scavenger receptor BI (SR-BI) as a critical mediator of free heme clearance. SR-BI binds heme and facilitates its hepatic uptake under pathological conditions. Mice lacking hepatic SR-BI exhibit impaired heme clearance and increased susceptibility to heme- and hemolysis-induced lethality. Pharmacological upregulation of hepatic SR-BI via imatinib or adenoviral delivery confers protection against heme toxicity. Using a humanized model of sickle cell disease (SCD), we further demonstrate that sickle hepatopathy significantly reduces hepatic SR-BI expression compared to non-SCD littermates, potentially increasing vulnerability to heme-induced injury. Notably, adenoviral-mediated SR-BI upregulation rescues SCD mice from heme toxicity. These findings reveal a previously unrecognized mechanism of heme detoxification via hepatic SR-BI and identify a promising therapeutic target for hemolytic disorders. One-Sentence SummaryIdentification of scavenger receptor BI as a targetable scavenger of heme in hemolysis

physiology↗

bioRxiv2025

Impaired Chylomicron Secretion Results in Reduced Body Fat and Increased Intestinal Fatty Acid Oxidation by Activation of Autophagy

Intestinal absorption of dietary lipid is essential for systemic lipid homeostasis; however, elevated postprandial plasma lipid levels are associated with obesity and increased risk for atherosclerotic cardiovascular disease. In humans and rodents, biological sex impacts dietary triglyceride absorption and males tend to have higher postprandial triglyceride levels compared to females, but the physiological basis for this is not well understood. Here, we show that the gene DENND5B is associated with body composition in humans and mice and that genetic deletion of Dennd5b in mice prevents postprandial plasma triglyceride elevations in both sexes. Our findings establish a role for this protein in intestinal chylomicron secretion and reveal a biological sex-biased differential impact of its deletion on body composition, dietary fatty acid uptake, and intestinal metabolism. Mechanistically, our findings implicate autophagy and mitochondrial beta oxidation in coping with enterocyte lipid accumulation due to impaired chylomicron secretion. This work extends the emerging concept that the intestinal epithelium may play a prominent role in oxidation of diet-derived fatty acids and suggests that this process may contribute to biological sex-based differences in postprandial lipemia and body composition. HighlightsO_LIThe DENND5B gene is required for dietary triglyceride absorption and is associated with metabolic phenotypes in humans and mice. C_LIO_LIDisruption of chylomicron secretion differentially affects body composition, dietary lipid absorption, and intestinal metabolic activity in male and female mice. C_LIO_LIIn mice, genetic disruption of Dennd5b results in lower body fat in both sexes, and increased lean mass only in males. C_LIO_LIMetabolic phenotypes in Dennd5b-deficient mice are driven by reduced absorption of dietary lipid characterized by enterocyte lipid retention and increased fecal lipid excretion. C_LIO_LIImpaired chylomicron secretion in Dennd5b-/- mice induces autophagy-mediated disposal of cellular triglyceride and increased fatty acid oxidation in intestinal tissue. C_LI

physiology↗

bioRxiv2025

Postoperative Stress Accelerates Atherosclerosis through Inflammatory Remodeling of the HDL Proteome and Impaired Reverse Cholesterol Transport

BACKGROUNDOver 10 million patients undergoing non-cardiac surgery annually experience major cardiovascular complications within 30 days, many due to destabilized atherosclerotic plaques. Reverse cholesterol transport (RCT), a key pathway for cholesterol removal by HDL and apoA-I, is critical in preventing plaque progression. While surgery-induced inflammation is known to impair HDL function, its effects on RCT and plaque stability remain unclear. METHODSTo isolate the impact of surgical inflammation, independent of blood loss, we developed an abdominal laparotomy model in apoE-/- mice on a Western diet, minimizing blood loss and avoiding perioperative blood sampling. We assessed plasma cholesterol efflux capacity, performed proteomic analysis of HDL, and analyzed atherosclerotic plaques for lipid content, perilipin-2 (PLIN2), cleaved-caspase-3 (c-Casp-3), and necrotic core expansion. A novel dual-label, dual-cell-type in vivo RCT model was developed to compare RCT from macrophage-derived (BMDMs) and vascular smooth muscle cells (VSMCs)-derived foam cells. Recombinant apoA-I (rApoA-I) was tested for therapeutic rescue of impaired RCT. RESULTSSurgery significantly reduced RCT for at least 48 hours, paralleled by a drop in cholesterol efflux capacity and inflammatory remodeling of HDL, marked by elevated serum amyloid A (SAA1/2) and reduced apoA-I. Plaques showed a 1.6-fold increase in intracellular lipids and PLIN2 expression at 24 hours post-surgery, with elevated c-Casp-3 indicating lipid-driven apoptosis. Foam cell analysis revealed increased PLIN2 in both CD45+ (leukocyte) and CD45- (non-leukocyte) subtypes, with leukocyte foam cells expressing higher PLIN2. c-Casp-3+ apoptotic cells were predominantly PLIN2high and of both leukocytic and non-leukocytic origin. By day 15, the necrotic core area increased by 1.5-fold with sustained loss of plaque cellularity. Using our dual-cell-type RCT model, we found that surgery significantly impaired BMDM RCT in vivo, while VSMC RCT remained largely unaffected, highlighting foam cell subtype-specific vulnerability to surgical inflammation. These findings were mirrored in general surgery patients, whose postoperative plasma exhibited markedly reduced cholesterol efflux capacity. In mice, rApoA-I treatment partially restored RCT and reduced plaque lipid accumulation. CONCLUSIONSSurgical inflammation acutely impairs HDL function and RCT, triggering lipid accumulation, foam cell apoptosis, and accelerated plaque destabilization independent of blood loss. Immediate restoration of apoA-I at the time of surgery, aiming to counteract the acute phase response, may offer a targeted strategy to reduce postoperative cardiovascular risk.

biochemistry↗

bioRxiv2025

ABCG5 ABCG8-independent mechanisms fail to maintain sterol balance in mice fed a high cholesterol diet

The ABCG5 ABCG8 (G5G8) sterol transporter opposes the accumulation of dietary xenosterols, but is also the primary mediator of biliary cholesterol secretion in the cholesterol elimination pathway. In humans and in mouse models of disrupted biliary cholesterol secretion, fecal neutral sterols remain constant, indicating the presence of a G5G8-independent mechanism for cholesterol excretion. Transintestinal cholesterol elimination (TICE) is thought to compensate for biliary G5G8 insufficiency. We sought to measure the compensatory increase in intestinal cholesterol secretion and provide mechanistic insight for how TICE maintains sterol balance in the absence of G5G8. Differences were not observed in fecal neutral sterols between control, acute, and chronic liver-specific G5G8 deficient mice (G5G8LKO). Cholesterol content did not differ at any point along the intestinal tract between genotypes. We also observed no change in the expression of apical or basolateral sterol transporting enzymes in the proximal small intestine. We then measured biliary and intestinal cholesterol secretion rates using cholesterol free and cholesterol enriched bile acid micelles as acceptors. While biliary cholesterol secretion was reduced, the intrinsic rate of intestinal cholesterol secretion did not differ between genotypes. G5G8LKO and whole-body G5G8-deficient mice were challenged with a cholesterol-containing diet. While control mice upregulate fecal neutral sterol excretion, G5G8LKO and G5G8-/- mice fail to do so and accumulate sterol in the liver and plasma. These studies indicate that while G5G8-independent mechanisms can mediate cholesterol excretion, TICE is not upregulated in response to a loss of hepatic G5G8 and is unable to compensate for hepatic or whole-body G5G8-deficiency in response to dietary cholesterol in mice.

physiology↗

bioRxiv2024

APOE4 alters the lipid droplet proteome and modulates droplet dynamics

Excess lipid droplet (LD) accumulation is associated with several pathological states, including Alzheimers disease (AD). However, the mechanism(s) by which changes in LD composition and dynamics contribute to pathophysiology of these disorders remains unclear. Apolipoprotein E (ApoE) is a droplet associated protein with a common risk variant (E4) that confers the largest increase in genetic risk for late-onset AD. E4 is associated with both increased neuroinflammation and excess LD accumulation. In the current study, we sought to quantitatively profile the lipid and protein composition of LDs between the neutral E3 and risk variant E4, to gain insight into potential LD-driven contributions to AD pathogenesis. Targeted replacement mice expressing human E3 or E4 were injected with saline or lipopolysaccharide (LPS), and after 24 hours, hepatic lipid droplets were isolated for proteomic and lipidomic analyses. Lipidomics revealed a shift in the distribution of glycerophospholipids in E4 LDs with a concomitant increase in phosphatidylcholine species, and overall, the baseline profile of E4 LDs resembled that of the LPS-treated groups. Quantitative proteomics showed that LDs from E4 mice are enriched for proteins involved in protein/vesicle transport but have decreased levels of proteins involved in fatty acid {beta}-oxidation. Interestingly, proteins associated with LDs showed substantial overlap with previously published lists of AD postmortem tissue and microglia omics studies, suggesting a potential role for LDs in modulating AD risk or progression. Given this, we exposed primary microglia from the same E3 or E4 mice to exogenous lipid, inflammatory stimulation, necroptotic N2A cells (nN2A), or a combination of treatments to evaluate LD formation and its impact on the cells immune state. Microglia from E4 mice accumulated more LDs in every condition tested - at baseline and following addition of fatty acids, LPS stimulation, or nN2As. E4 microglia also secreted significantly more cytokines (TNF, IL-1{beta}, IL-10) than E3 microglia in the control, oleic acid, and nN2A treatment conditions, yet showed a blunted response to LPS. In sum, these results suggest that E4 microglia accumulate more LDs compared to E3 microglia and that E4 is associated with a basal LD composition that resembles a pro-inflammatory cell. Together with the high overlap of the LD proteome with established AD-associated datasets, these data further support the idea that alterations in LD dynamics, particularly within microglia, may contribute to the increased risk for AD associated with APOE4.

physiology↗

bioRxiv2024

Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers Apolipoprotein B Containing Lipoproteins in Mice

Genome- and epigenome-wide association studies have associated variants and methylation status of carnitine palmitoyltransferase 1a (CPT1a) to reductions in very low-density lipoprotein (VLDL) cholesterol and triglyceride levels. We report significant associations between the presence of CPT1a SNPs and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild type and human apolipoprotein B100 (apoB)-transgenic mice with liver-specific deletion of Cpt1a (LKO) display lower circulating apoB levels consistent with reduced LDL-cholesterol (LDL-C) and LDL particle number. Despite a reduction in steady-state plasma lipids, VLDL-triglyceride (VLDL-TG) and cholesterol (VLDL-C) secretion rates are increased, suggesting accelerated clearance of apoB-containing lipoproteins (apoB-LPs) in LKO mice. Mechanistic approaches show greater peroxisome proliferator activated receptor (PPAR) signaling which favors enhanced lipoprotein lipase-mediated metabolism of apoB-LPs, including increases in ApoCII and ApoAIV and reductions in ApoCIII & Angptl3. These studies provide mechanistic insight linking genetic variants and methylation status of CPT1a to reductions in circulating apoB-LPs in humans. HIGHLIGHTSO_LILoss-of-function SNPs in CPT1a associate with reductions in plasma cholesterol in humans C_LIO_LIHepatic Cpt1a expression positively associates with plasma cholesterol levels across inbred strains of mice C_LIO_LILiver-specific Cpt1a deficiency lowers circulating apoB, plasma cholesterol, LDL-C, and LDL particle number C_LIO_LICpt1a ablation activates PPAR and favors clearance of apoB-containing lipoproteins C_LI

physiology↗

bioRxiv2023

Enhancement of High-Density Lipoprotein-Associated Protease Inhibitor Activity Prevents Atherosclerosis Progression

BackgroundInflammatory cells within atherosclerotic lesions secrete various proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. The relative contributions of specific proteases to atherogenesis is not well understood. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We have previously reported interaction of endogenous protease-inhibitor proteins with high-density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as an endogenous modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression. MethodsWe designed an HDL-targeting protease inhibitor (HTPI) that binds to HDL and confers elastase inhibitor activity. Lipoprotein binding and the impact of HTPI on atherosclerosis was examined using mouse models. ResultsHTPI is a small (1.6 kDa) peptide with an elastase inhibitor domain, a soluble linker, and an HDL-targeting domain. When incubated with human plasma ex vivo, HTPI predominantly binds to HDL. Intravenous administration of HTPI to mice resulted in its binding to plasma HDL and increased elastase inhibitor activity on isolated HDL. Accumulation of HTPI within plaque was observed after systemic administration to Apoe-/- mice. To examine the effect of HTPI treatment on atherosclerosis, prevention and progression studies were performed using Ldlr-/- mice fed Western diet. In both study designs, HTPI-treated mice had reduced lipid deposition in plaque. Histology and immunofluorescence staining of aortic root sections were used to examine the impact of HTPI on lesion morphology and inflammatory features. ConclusionsThese data support the hypothesis that HDL-associated anti-elastase activity can improve the atheroprotective potential of HDL and highlight the potential utility of HDL enrichment with anti-protease activity as an approach for stabilization of atherosclerotic lesions.

physiology↗

bioRxiv2021

Identification of Target Objects from Gaze Behavior during a Virtual Navigation Task

Eye tracking has been an essential tool within the vision science community for many years. However, the majority of studies involving eye-tracking technology employ a relatively passive approach through the use of static imagery, prescribed motion, or video stimuli. This is in contrast to our everyday interaction with the natural world where we navigate our environment while actively seeking and using task-relevant visual information. For this reason, vision researchers are beginning to use virtual environment platforms, which offer interactive, realistic visual environments while maintaining a substantial level of experimental control. Here, we recorded eye movement behavior while participants freely navigated through a complex virtual environment. Within this environment, participants completed a visual search task where they were asked to find and count occurrence of specific targets among numerous distractor items. We assigned each participant into one of four target groups: Humvees, motorcycles, aircraft, or furniture. Our results show a significant relationship between gaze behavior and target objects across subject groups. Specifically, we see an increased number of fixations and increase dwell time on target relative to distractor objects. In addition, we included a divided attention task to investigate how search patterns changed with the addition of a secondary task. With increased cognitive load, subjects slowed their speed, decreased gaze on objects, and increased the number of objects scanned in the environment. Overall, our results confirm previous findings from more controlled laboratory settings and demonstrate that complex virtual environments can be used for active visual search experimentation, maintaining a high level of precision in the quantification of gaze information and visual attention. This study contributes to our understanding of how individuals search for information in a naturalistic virtual environment. Likewise, our paradigm provides an intriguing look into the heterogeneity of individual behaviors when completing an un-timed visual search task while actively navigating.

neuroscience↗

bioRxiv2019

Interferons drive development of novel interleukin-15-responsive macrophages in the uterus

Disruption in homeostasis of interleukin-15 (IL-15) is linked to poor maternal and fetal outcomes during pregnancy. The only cells described to respond to IL-15 at the early maternal-fetal interface have been natural killer (NK) cells. We now show a novel population of macrophages, evident in several organs but enriched in the uterus of mice and humans, expressing the {beta} chain of the IL-15 receptor complex (CD122) and responding to IL-15. CD122+ macrophages (CD122+Macs) are morphologic, phenotypic, and transcriptomic macrophages that can derive from bone marrow monocytes. CD122+Macs develop in the uterus and placenta with kinetics that mirror interferon (IFN) activity at the maternal-fetal interface. Macrophage colony-stimulating factor (M-CSF) permits macrophages to express CD122, and IFNs are sufficient to drive expression of CD122 on macrophages. Neither Type-I nor Type-II IFNs are required to generate CD122+Macs, however. In response to IL-15, CD122+Macs activate the ERK signaling cascade and enhance production of proinflammatory cytokines after stimulation with the Toll-like receptor 9 agonist CpG. Finally, we provide evidence of human cells that phenocopy murine CD122+Macs in secretory phase endometrium during the implantation window and in first-trimester uterine decidua. Our data support a model wherein IFNs local to the maternal-fetal interface direct novel IL-15-responsive macrophages with the potential to mediate IL-15 signals critical for optimal outcomes of pregnancy. The microarray data presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE132353.

immunology↗

bioRxiv2019

Decoding P300 Variability using Convolutional Neural Networks

Deep convolutional neural networks (CNN) have previously been shown to be useful tools for signal decoding and analysis in a variety of complex domains, such as image processing and speech recognition. By learning from large amounts of data, the representations encoded by these deep networks are often invariant to moderate changes in the underlying feature spaces. Recently, we proposed a CNN architecture that could be applied to electroencephalogram (EEG) decoding and analysis. In this article, we train our CNN model using data from prior experiments in order to later decode the P300 evoked response from an unseen, hold-out experiment. We analyze the CNN output as a function of the underlying variability in the P300 response and demonstrate that the CNN output is sensitive to the experiment-induced changes in the neural response. We then assess the utility of our approach as a means of improving the overall signal-to-noise ratio in the EEG record. Finally, we show an example of how CNN-based decoding can be applied to the analysis of complex data.

neuroscience↗